C60-based Multivalent Glycoporphyrins Inhibit SARS-CoV-2 Specific Interaction with the DC-SIGN Transmembrane Receptor.

Since WHO has declared the COVID-19 outbreak a global pandemic, nearly seven million deaths have been reported. This efficient spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is facilitated by the ability of the spike glycoprotein to bind multiple cell membrane receptors. Although ACE2 is identified as the main receptor for SARS-CoV-2, other receptors could play a role in viral entry. Among others, C-type lectins such as DC-SIGN are identified as efficient trans-receptor for SARS-CoV-2 infection, so the use of glycomimetics to inhibit the infection through the DC-SIGN blockade is an encouraging approach. In this regard, multivalent nanostructures based on glycosylated [60]fullerenes linked to a central porphyrin scaffold have been designed and tested against DC-SIGN-mediated SARS-CoV-2 infection. First results show an outstanding inhibition of the trans-infection up to 90%. In addition, a deeper understanding of nanostructure-receptor binding is achieved through microscopy techniques, high-resolution NMR experiments, Quartz Crystal Microbalance experiments, and molecular dynamic simulations.

Immune evasion through Toll-like receptor 4: The role of the core oligosaccharides from α2-Proteobacteria atypical lipopolysaccharides.

Lipopolysaccharides (LPS) are major players in bacterial infection through the recognition by Toll-like receptor 4 (TLR4). The LPS chemical structure, including the oligosaccharide core and the lipid A moiety, can be strongly influenced by adaptation and modulated to assure bacteria protection, evade immune surveillance, or reduce host immune responses. Deep structural understanding of TLRs signaling is essential for the modulation of the innate immune system in sepsis control and inflammation, during bacterial infection. To advance this knowledge, we have employed computational techniques to characterize the TLR4 molecular recognition of atypical LPSs from different opportunistic members of α2-Proteobacteria, including Brucella melitensis, Ochrobactrum anthropi, and Ochrobactrum intermedium, with diverse immunostimulatory activities. We contribute to unraveling the role of uncommon lipid A chemical features such as bearing very long-chain fatty acid chains, whose presence has been rarely reported, on modulating the proper heterodimerization of the TLR4 receptor complex. Moreover, we further evaluated the influence of the different oligosaccharide cores, including sugar composition and net charge, on TLR4 activation. Our studies contribute to elucidating, from the molecular and biological perspectives, the impact of the α2-Proteobacteria LPS cores and the chemical structure of the atypical lipid A for immune system evasion in opportunistic bacteria.

Treatment with the senolytics dasatinib/quercetin reduces SARS-CoV-2-related mortality in mice.

The enormous societal impact of the ongoing COVID-19 pandemic has been particularly harsh for some social groups, such as the elderly. Recently, it has been suggested that senescent cells could play a central role in pathogenesis by exacerbating the pro-inflammatory immune response against SARS-CoV-2. Therefore, the selective clearance of senescent cells by senolytic drugs may be useful as a therapy to ameliorate the symptoms of COVID-19 in some cases. Using the established COVID-19 murine model K18-hACE2, we demonstrated that a combination of the senolytics dasatinib and quercetin (D/Q) significantly reduced SARS-CoV-2-related mortality, delayed its onset, and reduced the number of other clinical symptoms. The increase in senescent markers that we detected in the lungs in response to SARS-CoV-2 may be related to the post-COVID-19 sequelae described to date. These results place senescent cells as central targets for the treatment of COVID-19, and make D/Q a new and promising therapeutic tool.

Early p38 Activation Regulated by MKP-1 Is Determinant for High Levels of IL-10 Expression Through TLR2 Activation.

Toll-like receptors (TLRs) play a crucial role in the recognition of pathogen-derived components as a first line of defense against infections. It has been suggested that depending on the nature of the pathogens, TLRs activation induce a distinct cytokine profile that may contribute to the polarization of the acquired immune response. Here, we investigated the early MAPK signaling activation via TLR4 and TLR2 receptors and its impact in differential cytokine profile by macrophages. We found that TLR2 ligands activated MAPKs p38 and ERK earlier compared to the TLR4 ligand LPS in macrophages. Higher IL-10/IL-12 and IL-10/TNF-α ratios were also observed at later time points in response to TLR2 ligands compared to LPS. The results also indicate an earlier activation of the phosphatase MKP-1 and that MKP-1 KO macrophages show a prolongation in p38 phosphorylation in response to TLR2 stimulation. Furthermore, p38 is critical for IL-10 expression in response to TLR2 ligands, which triggers the macrophage change to a M2 and regulatory phenotype in contrast to the M1 phenotype induced by TLR4 activation. Therefore, the early TLR2-mediated p38 induction contributes for the high IL-10 production, likely as a virulence strategy to suppress host Th1 response against certain types of pathogens.

Induction of TLR4/TLR2 Interaction and Heterodimer Formation by Low Endotoxic Atypical LPS.

The Toll-like receptor 4 (TLR4)/myeloid differentiation protein-2 (MD-2) complex is considered the major receptor of the innate immune system to recognize lipopolysaccharides (LPSs). However, some atypical LPSs with different lipid A and core saccharide moiety structures and compositions than the well-studied enterobacterial LPSs can induce a TLR2-dependent response in innate immune cells. Ochrobactrum intermedium, an opportunistic pathogen, presents an atypical LPS. In this study, we found that O. intermedium LPS exhibits a weak inflammatory activity compared to Escherichia coli LPS and, more importantly, is a specific TLR4/TLR2 agonist, able to signal through both receptors. Molecular docking analysis of O. intermedium LPS predicts a favorable formation of a TLR2/TLR4/MD-2 heterodimer complex, which was experimentally confirmed by fluorescence resonance energy transfer (FRET) in cells. Interestingly, the core saccharide plays an important role in this interaction. This study reveals for the first time TLR4/TLR2 heterodimerization that is induced by atypical LPS and may help to escape from recognition by the innate immune system.

Assessment of a Novel Vaccine Against Rabbit Hemorrhagic Disease Virus in Young Rabbits.

Rabbit hemorrhagic disease virus (RHDVb) is the new variant of the classical RHDV, a virulent pathogen responsible for an acute disease in young rabbits. The virus invades internal organs, especially the liver, spleen, kidneys, and gut; prevents coagulation; and causes liver necrosis. This eventually leads to quick death of the animal because of hemorrhage. In this study, we evaluated the effects of a new vaccine against RHDVb in rabbits at a young age, after experimental infection using four different viral isolates. Our findings show that the vaccine had a protective effect with survival rates reaching 80-100% against the different isolates. These results suggest that this vaccine, when applied to young animals, is an effective tool to protect against the disease caused by RHDVb in rabbitries.

Experiencias de los enfermeros en el desempeño de su rol profesional / Nurse ́s experiences in performing their professional role

Introdución: cada vez son más los hombres que deciden ejercer la profesión de enfermería, lo cual supone cambios en la visión que tienen los propios enfermeros sobre su desempeño. Objetivo: describir las experiencias de los enfermeros en el desempeño de su profesión. Material y metodos: se empleó un diseño de investigación cualitativa, de corte fenomenológico descriptivo. Se realizó una entrevista semiestructurada a ocho profesionales de enfermería de sexo masculino que se desempeñan en algún rol de la profesión de enfermería. Resultados: la mayoría de los enfermeros entrevistados manifestaron: es un reto estar en enfermería en el contexto social actual, debido a las opiniones desfavorables respecto a su desempeño. Sin embargo, también coinciden en sentirse identificados con la carrera, cuidado y quehacer de la enfermería Conclusión: los profesionales de enfermería varones se enfrentan aún con varios retos en el camino de un reconocimiento cabal de su quehacer profesional.